Reddistatin - instructions for use, dose, side effects, contraindications

film sheath: opadrai II yellow 32K520046 (hypromellose 15 cP 40.0%, lactose monohydrate 28.0%, titanium dioxide (E171) 20.75%, triacetin 8.0%, dye quinoline yellow (E104) 2.75%, dye red charming (E129) 0.45%, dye indigo carmine (E132) 0.05%) 5.25 mg.

Each tablet, film-coated, 10 mg contains:

Active substance: rosuvastatin calcium 10.40 mg (in terms of rosuvastatin 10 mg).

Excipients: cellulose microcrystalline 38.54 mg, lactose monohydrate 89.06 mg, crospovidone 7.50 mg, meglumine 3.00 mg, magnesium stearate 1.50 mg;

film sheath: Opaprai II pink 32K540017 (lactose monohydrate 40.0%, hypromellose 15 cp 28.0%, titanium dioxide (E171) 22.22%, triacetin 8.0%, dye red charming (E129) 0.9%, dye sunset sunset yellow (E110) 0.8%, dye indigo carmine (E132) 0.08%) 5.25 mg.

Each tablet, film-coated, 20 mg contains:

Active substance: rosuvastatin calcium 20,80 mg (in terms of rosuvastatin 20 mg).

Excipients: cellulose microcrystalline 77.08 mg, lactose monohydrate 178.12 mg, crospovidone 15.00 mg, meglumine 6.00 mg, magnesium stearate 3.00 mg;

Each tablet, film-coated, 40 mg contains:

Active substance: rosuvastatin calcium 41,60 mg (in terms of rosuvastatin 40 mg).

Excipients: cellulose microcrystalline 77.08 mg, lactose monohydrate 157.32 mg, crospovidone 15.00 mg, meglumine 6.00 mg, magnesium stearate 3.00 mg;

film sheath: opadrai II pink 32K540017 (lactose monohydrate 40.0%, hypromellose 15 cP 28.0%,titanium dioxide (E171) 22.22%, triacetin 8.0%, dye red charming (E129) 0.9%, dye sunset yellow (E110) 0.8%, dye indigo carmine (E132) 0.08%) 10 , 50 mg

Description:

Tablets 5 mg

Round, biconvex tablets covered with a film coat from pale yellow to yellow, with an embossed "5" on one side and "Ύ" on the other side. On the cross-section - the core is from white to almost white.

Tablets 10 mg

Round, biconvex tablets, covered with a film sheath from pale pink to pink, with an embossed "10" on one side and "Ύ" on the other side. On the cross-section - the core is from white to almost white.

Tablets 20 mg

Round, biconvex tablets covered with a film membrane from pale pink to pink, with an embossed "20" on one side and "Ύ" on the other side. On the cross-section - the core is from white to almost white.

Tablets 40 mg

Oval, biconvex tablets covered with a film sheath from pale pink to pink, with an embossed "40" on one side and "Ύ" on the other side. On the cross-section - the core is from white to almost white.

Pharmacotherapeutic group:Hypolipidaemic agent - HMG-CoA-reductase inhibitor

ATX: & nbsp

C.10.A.A Inhibitors of HMG-CoA reductase

C.10.A.A.07 Rosuvastatin

Pharmacodynamics:

Mechanism of action

Rosuvastatin is a selective, competitive inhibitor of HMG-CoA reductase, an enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A to mevalonic acid, the precursor of cholesterol.

Rosuvastatin increases the number of "liver" receptor low-density lipoprotein (LDL) on the cell surface, increasing the catabolism of LDL and grip, which in turn leads to inhibition of the synthesis of very low density lipoproteins (VLDL), thereby reducing the total amount of VLDL and LDL.

Pharmacodynamics

Rosuvastatin decreases the increased content of LDL-cholesterol (LDL-C), total cholesterol and triglycerides (TG) and increases high-density lipoprotein cholesterol (HDL-C), and also reduces the concentration of apolipoprotein B (apoB) neLPVP-cholesterol, HS- VLDL, triglycerides, VLDL and increases the concentration of apolipoprotein AI (ApoA-I), see. table 1, decreases the ratio of LDL-C / HDL-C, total cholesterol / cholesterol-HDL cholesterol and LDL-neLPVP / cholesterol-HDL cholesterol and the ratio of apoB / ApoA -I.

The therapeutic effect develops within one week after the beginning of therapy with the drug, after 2 weeks of treatment it reaches 90% of the maximum possible effect.

The maximum therapeutic effect is usually achieved by the 4th week of therapy and is maintained with further regular intake of the drug.

Table 1. Dose-dependent effect in patients with primary hypercholesterolemia (type Ha and Hb by Fredrickson). Average adjusted percentage change compared to the original value

Dose	amount patients	HS-LDL	General HS	HS-HDL	TG	HS-non-HDL	APOP	ApoA-I
Placebo	13	-7	-5	3	-3	-7	-3	-
5 mg	17	-45	-33	13	-35	-44	-38	4
10 mg	17	-52	-36	14	-10	-48	-42	4
20 mg	17	-55	-40	8	-23	-51	-46	5
40 mg	18	-63	-46	10	-28	-60	-54	0

Clinical efficacy

Rosuvastatin is effective in adult patients with hypercholesterolemia with or without symptoms of hypertriglyceridemia, regardless of their race, gender or age, including patients with diabetes mellitus and familial hypercholesterolemia.

In 80% of patients with hypercholesterolemia IIa and IIb type (according to the average initial concentration of LDL-C, about 4.8 mmol / L), when taking the drug at a dose of 10 mg, the concentration of LDL-C is less than 3 mmol / l.

In patients with heterozygous familial hypercholesterolemia who took rosuvastatin in doses of 20 to 80 mg, there is a positive dynamics of lipid profile (a study involving 435 patients).After titration to a daily dose of 40 mg (12 weeks of therapy), the concentration of LDL-C is decreased by 53%. In 33% of patients the concentration of LDL-C is less than 3 mmol / l.

In patients with homozygous familial hypercholesterolemia who took rosuvastatin in doses of 20 and 40 mg, the average decrease in the concentration of LDL-C is 22%.

In patients with hypertriglyceridemia with an initial TG concentration of 273 to 817 mg / dL, rosuvastatin in a dose of 5 mg to 40 mg once a day for six weeks, the concentration of TG in blood plasma decreased significantly.

The additive effect is noted in combination with fenofibrate for TG and nicotinic acid in lipid-lowering doses for the content of cholesterol-lowering cholesterol (see also section "Special instructions").

In patients with a low risk of developing coronary heart disease (CHD) (the risk of the Framingham scale is less than 10% over a period of more than 10 years), with an average LDL cholesterol concentration of 4.0 mmol / L (154.5 mg / dL) and subclinical atherosclerosis , which was estimated by the thickness of the complex "intima-media" of carotid arteries - TKIM, rosuvastatin in a dose of 40 mg / day significantly slowed the progression of the maximum TKIM for 12 segments of the carotid artery compared with placebo with a difference of -0.0145 mm / year (95% confidence interval (CI): -0.0196 to -0.0093; p <0.001).A dose of 40 mg should be given only to patients with severe hypercholesterolemia and a high risk of cardiovascular disease (CVD).

The results of a study on the use of HMG-CoA reductase inhibitors (statins) for primary prevention showed that rosuvastatin significantly reduced the risk of developing cardiovascular complications with a relative risk reduction of 44%. The effectiveness of therapy was noted after 6 months of the drug. There was a statistically significant 48% reduction in the combined criteria, including cardiovascular mortality, stroke and myocardial infarction, a 54% decrease in the incidence of fatal or nonfatal myocardial infarction and 48% - fatal or nonfatal stroke. Total mortality decreased by 20% in the rosuvastatin group.

Pharmacokinetics:

Absorption and distribution

The maximum concentration of rosuvastatin in the blood plasma is reached approximately 5 hours after ingestion. Absolute bioavailability is approximately 20%.

Rosuvastatin is metabolized primarily by the liver, which is the main site for the synthesis of cholesterol and the metabolism of LDL-C.The volume distribution of rosuvastatin is approximately 134 liters. About 90% of rosuvastatin binds to blood plasma proteins, mainly albumin.

Metabolism

It is subject to limited metabolism (about 10%). Rosuvastatin is a non-core substrate for metabolism by isoenzymes of the cytochrome P450 system. The main isoenzyme involved in the metabolism of rosuvastatin is CYP2C9. Isozymes CYP2C19, CYP3A4 and CYP2D6 are less involved in metabolism. The main revealed metabolites of rosuvastatin are N-desmethylrozuvastatin and lactone metabolites. Nis less than 50% less active than rosuvastatin, lactone metabolites are pharmacologically inactive. More than 90% of the pharmacological activity of inhibiting the circulating HMG-CoA reductase is provided by rosuvastatin, the rest - by its metabolites.

Excretion

About 90% of the dose of rosuvastatin is excreted unchanged through the intestine (including absorbed and unabsorbed rosuvastatin). The rest is excreted by the kidneys. Plasma half-life (T₁_/₂) is approximately 19 hours.The half-life does not change with an increase in the dose of the drug. The average geometric plasma clearance is approximately 50 l / h (coefficient of variation 21.7%). As with other inhibitors of HMG-CoA reductase, a membrane cholesterol transporter involved in the hepatic elimination of rosuvastatin plays an important role in the hepatic elimination of rosuvastatin.

Linearity

The systemic exposure of rosuvastatin increases in proportion to the dose. Pharmacokinetic parameters do not change with daily intake.

Special populations of patients

Age and gender

Sex and age do not have a clinically significant effect on the pharmacokinetics of rosuvastatin.

Ethnic groups

Pharmacokinetic studies showed approximately a twofold increase in the median area under the pharmacokinetic curve "concentration-time" (AUC) and the maximum concentration in the blood plasma (C_mOh) rosuvastatin in patients of the Mongoloid race (Japanese, Chinese, Filipinos, Vietnamese and Koreans) compared with Caucasians; Hindus show an increase in median AUC and C_mOhin 1,3 times.

Pharmacokinetic analysis did not reveal clinically significant differences in pharmacokinetics among representatives of the Caucasoid and Negroid race.

Renal insufficiency

In patients with mild to moderate renal failure, the plasma concentration of rosuvastatin or N-desmethyl-rosuvastatin does not change significantly. In patients with severe renal failure (creatinine clearance less than 30 ml / min), the concentration of rosuvastatin in the blood plasma is 3 times higher, and the concentration N-desmethylrozuvastatin is 9 times higher than in healthy volunteers. The concentration of rosuvastatin in blood plasma in patients on hemodialysis was approximately 50% higher than in healthy volunteers.

Liver failure

Patients with different stages of hepatic insufficiency did not have an increase in the half-life of rosuvastatin (in patients with 7 points or lower on the Child-Pugh scale). In two patients with the 8th and 9th points on the Child-Pugh scale, the half-life was increased by at least 2 times. The experience with rosuvastatin in patients with more than 9 points on the Child-Pugh scale is not available.

Genetic polymorphism

Inhibitors of HMG-CoA reductase, including, rosuvastatin, bind to transport proteins OATP1B1 (the polypeptide of organic anion transport, involved in the capture of statins by hepatocytes) and BCRP (efflux conveyor). In carriers of genotypes SLC01B1 (OATP1B1) p.521NC and ABCG2 (BCRP) p.421AA there was an increase in exposure (AUC) to rosuvastatin in 1,6 and 2,4 times, respectively, in comparison with the carriers of genotypes SLC01B1 p.521TT ABCG2 p.421CC.

Indications:

- Primary hypercholesterolemia according to Fredrickson classification (type II(including familial heterozygous hypercholesterolemia) or mixed hypercholesterolemia (type Hb) as a supplement to the diet, when diet and other non-pharmacological therapies (eg exercise, weight loss) are inadequate.

- Family homozygous hypercholesterolemia as a supplement to diet and other lipid-lowering therapy (eg, LDL-apheresis) or in cases when such therapy is not effective enough.

- Hypertriglyceridemia (type IV according to Fredrickson's classification) as a supplement to the diet.

- To slow the progression of atherosclerosis as a supplement to the diet in patients who are shown therapy to reduce the concentration of total cholesterol and LDL-C.

- Primary prevention of major cardiovascular complications (stroke, heart attack, arterial revascularization) in adult patients without clinical signs of IHD, but with an increased risk of its development (age over 50 for men and over 60 for women, increased concentration of C-reactive protein ( more than 2 mg / L) with at least one of additional risk factors, such as hypertension, low concentration of HDL-C, smoking, family history of early development of coronary artery disease).

Contraindications:

For a daily dose of 5 mg, 10 mg and 20 mg:

- increased sensitivity to rosuvastatin or any of the components of the drug;

- lactose intolerance, lactase deficiency or glucose-galactose malabsorption (since the preparation contains lactose);

- age under 18 years (effectiveness and safety not established);

- liver diseases in the active phase, including a persistent increase in the activity of "liver" transaminases and any increase in the activity of "hepatic" transaminases in the serum more than 3 times compared with the upper limit of the norm;

- severe renal dysfunction (CC less than 30 ml / min);

- myopathy;

- simultaneous administration of cyclosporine;

- in women: pregnancy, the period of breastfeeding, the lack of reliable methods of contraception;

- patients who are predisposed to the development of myotoxic complications.

For a daily dose of 40 mg:

- increased sensitivity to rosuvastatin or any of the components of the drug;

- presence of risk factors for the development of myopathy / rhabdomyolysis (moderate renal failure of less than 60 ml / min), hypothyroidism, history of myopathy (including hereditary forms), myotoxicity when taking other inhibitors of HMG-CoA reductase or fibrates in anamnesis, excessive admission alcohol, a condition that can lead to an increase in the plasma concentration of rosuvastatin, the simultaneous administration of fibrates, the use of Mongoloid races in patients);

- simultaneous administration of cyclosporine;

- in women: pregnancy, the period of breastfeeding, the lack of reliable methods of contraception;

- use in patients predisposed to the development of myotoxic complications;

- lactose intolerance, lactase deficiency or glucose-galactose malabsorption (the preparation contains lactose);

- age under 18 years (effectiveness and safety not established);

Carefully:

For a daily dose of 5 mg, 10 mg and 20 mg

The presence of a risk of myopathy / rhabdomyolysis - renal failure, hypothyroidism; personal or family history of hereditary muscle diseases and a previous history of muscle toxicity with the use of other inhibitors of HMG-CoA reductase (statins) or fibrates; excessive use of alcohol; conditions in which there was an increase in the plasma concentration of rosuvastatin; age over 65; liver disease in history; sepsis; arterial hypotension; extensive surgical interventions; injuries; severe metabolic, endocrine or electrolyte disorders; uncontrolled convulsive seizures; race (Mongoloid race); simultaneous reception of fibrates.

For a daily dose of 40 mg

The presence of a risk of myopathy / rhabdomyolysis - renal failure of mild severity (QC more than 60 ml / min); age over 65years; liver disease in history; sepsis; arterial hypotension; extensive surgical interventions; injuries; severe metabolic, endocrine or electrolyte disorders; uncontrolled epilepsy.

Application in pediatric practice

The effectiveness and safety of the drug in children under 18 years of age is not established. Experience in the use of the drug in pediatric practice is limited to a small number of children (8 years and older) with family homozygous hypercholesterolemia. Currently, it is not recommended to apply rosuvastatin in children under 18 years.

Pregnancy and lactation:

Rosuvastatin is contraindicated in pregnancy and during breastfeeding.

Women of reproductive age should use reliable and adequate methods of contraception.

Since cholesterol and other cholesterol biosynthesis products are of great importance for fetal development, the potential risk of HMG-CoA reductase inhibition is greater than the benefit of using the drug in pregnant women.

If the pregnancy is confirmed during the therapy, the drug should be stopped immediately.

Data on the allocation of rosuvastatin with breast milk are not available, therefore, during breast-feeding the drug should be discontinued.

Dosing and Administration:

Inside. At any time of the day, regardless of food intake. The tablet can not be chewed, chopped, swallowed whole, washed down with water.

Before starting therapy, the patient should begin to observe the standard hypocholesterolemic and continue to observe it throughout the treatment period. The dose of the drug should be selected individually, depending on the purpose of therapy and the therapeutic response to treatment, taking into account modern generally accepted recommendations for target lipid concentrations.

The recommended starting dose for patients starting to take rosuvastatin, or for patients transferred from other HMG-CoA reductase inhibitors, should be 5 or 10 mg once a day. When choosing the initial dose should be guided by individual cholesterol and take into account the possible risk of cardiovascular complications, as well as the potential risk of side effects. If necessary, after 4 weeks, the dose may be increased (see section "Pharmacodynamics").

In connection with the possible development of side effects when taking a dose of 40 mg compared with lower doses of the drug (see section "Side effect"), an increase in the dose of up to 40 mg after additional dosing above the recommended initial dose for 4 weeks of therapy can be performed only in patients with severe hypercholesterolemia and a high risk of cardiovascular complications (especially in patients with familial hypercholesterolemia) , who did not achieve the desired result of therapy when taking a dose of 20 mg, and which will be under the supervision of a doctor (see section "Special instructions"). It is recommended especially careful monitoring of patients receiving the drug in a dose of 40 mg.

Do not administer a dose of 40 mg to patients who have not previously consulted a doctor. After 2-4 weeks of therapy and / or with an increase in the dose of the drug, it is necessary to monitor the lipid metabolism parameters, if necessary, the dose should be adjusted.

Elderly patients

No dose adjustment is required.

Patients with renal insufficiency

In patients with mild or moderate renal insufficiency, dose adjustment is not required.In patients with severe renal failure (CC less than 30 ml / min), the use of the drug is contraindicated. Contraindicated the use of the drug in a dose of 40 mg to patients with moderate renal dysfunction with KK 30-60 ml / min (see the section "special instructions"and"Pharmacodynamics") Patients with moderate renal dysfunction are recommended an initial dose of 5 mg.

Patients with hepatic insufficiency

The drug is contraindicated in patients with liver disease in the active phase (see section "PContraindications ").

Special Populations

Ethnic groups

When studying the pharmacokinetic parameters of rosuvastatin in patients belonging to different ethnic groups, there was an increase in the systemic concentration of rosuvastatin among Japanese and Chinese (see "Special instructions"). This fact should be taken into account when prescribing the drug to this group of patients. When appointing doses of 10 mg and 20 mg, the recommended initial dose of the drug for patients of the Mongoloid race is 5 mg. Contraindicated the appointment of the drug in a dose of 40 mg to patients of the Mongoloid race (see section "Contraindications").

Genetic polymorphism

In carriers of genotypes SLCOIBI (OATP1B1) p.521CC and ABCG2 (BCRP) p.421AA there was an increase in exposure (AUC) to rosuvastatin in comparison with carriers of genotypes SLCOIBI from.521TT ABCG2 p.421CC. For patients carrying genotypes p.521SS or p.421AA the recommended maximum dose of rosuvastatin is 20 mg once daily (see sections "Pharmacokinetics", "Special instructions" and "Interaction with other drugs and other types of drug interactions").

Patients, predisposed to myopathy

Contraindicated the appointment of the drug in a dose of 40 mg to patients with factors that may indicate a predisposition to the development of myopathy (see section "Contraindications"), When appointing doses of 10 mg and 20 mg, the recommended initial dose for this group of patients is 5 mg (see section "Contraindications").

Concomitant therapy

Rosuvastatin binds to various transport proteins (in particular, to OATP1B1 and BCRP). When rosuvastatin is used together with medicinal products (such as ciclosporin, some HIV protease inhibitors, including a combination of ritonavir with atazanavir, lopinavir, and / or tipranavir), which increase the concentration of rosuvastatin in plasma by interacting with transport proteins, may increase the risk of myopathy, including rhabdomyolysis.sections "Special instructions" and "Interaction with other medicinal products and other types of drug interactions"). It should be familiar with the instructions for the use of these drugs before their appointment in conjunction with rosuvastatin. In such cases, the possibility of prescribing alternative therapies or temporarily stopping rosuvastatin should be evaluated. If joint use is necessary, the benefit-risk ratio of concomitant therapy with rosuvastatin should be assessed and the possibility of reducing its dose should be considered (see "Interaction with Other Drugs and Other Drug Interactions").

Side effects:

Side effects observed with the use of rosuvastatin, usually expressed slightly and pass independently. As with other inhibitors of HMG-CoA reductase, the incidence of side effects is mainly dose-dependent,

The frequency of undesirable effects is as follows: often (1/10 - 1/100 of prescriptions); infrequently (1/100 - 1/1000 appointments); rarely (1/1000 - 1/10 000 appointments), very rarely (<1/10 000); frequency is unknown (can not be calculated from available data).

Violations of the blood and lymphatic system

Rarely - thrombocytopenia.

Disturbances from the nervous system

Often - headache, dizziness; very rarely - peripheral neuropathy, loss or loss of memory; frequency is unknown - sleep disturbance, including insomnia and "nightmarish" dreams.

Disorders from the psyche

The frequency is unknown - depression.

Disorders from the digestive system

Often - constipation, nausea, pain in the abdomen; infrequently - vomiting; rarely - pancreatitis; frequency is unknown - diarrhea.

Disturbances from the liver and bile ducts

Rarely - transient increase in the activity of "liver" transaminases in a small number of patients; very rarely - hepatitis, jaundice.

Disturbances from the respiratory system

The frequency is unknown - cough, dyspnea.

Immune system disorders

Rarely - reactions of hypersensitivity, including angioedema.

Disorders from the endocrine system

Often - type 2 diabetes.

Disturbances from musculoskeletal and connective tissue

Often - myalgia; rarely - myopathy (including myositis), rhabdomyolysis (in patients treated at doses> 20 mg per day); very rarely - arthralgia, tendopathy, possibly with a rupture of tendons; frequency unknown - immune-mediated necrotizing myopathy.

Disturbances from the skin and subcutaneous tissues

Infrequent - itchy skin, skin rash, hives; frequency is unknown - Stephen-Johnson syndrome.

Disorders from the kidneys and urinary tract

Often - proteinuria (with a frequency of more than 3% in patients receiving a dose of 40 mg), decreasing in the course of therapy and not associated with the onset of kidney disease, urinary tract infection; very rarely - hematuria.

Violations of the genitals and mammary gland

Very rarely - gynecomastia.

Impact on indicators of laboratory and instrumental research

Infrequently - transient dose-dependent increase in serum CPK, CPK (with an increase of more than 5 times compared with the upper limit of normal therapy should be temporarily suspended), increasing the concentration of glycated hemoglobin in the blood plasma; frequency unknown - thyroid dysfunction, increased glucose concentration, bilirubin, alkaline phosphatase activity, gamma-glutamyl transpeptidase.

Other

Often - asthenia; frequency unknown - peripheral edema.

The use of some statins

The following side effects have been reported with the use of some statins: erectile dysfunction; single cases of interstitial lung disease,especially with prolonged use; Type 2 diabetes mellitus: frequency depends on the presence or absence of risk factors (fasting blood glucose 5,6 - 6,9 mmol / l, body mass index (BMI)> 30 kg / m², hypertriglyceridemia, arterial hypertension in the anamnesis.

Overdose:

There is no specific treatment for an overdose of rosuvastatin. In case of overdose, it is recommended to carry out symptomatic treatment and supporting functions of vital organs and systems of the event. It is necessary to monitor the liver function and the activity of CK. Hemodialysis in this case is probably ineffective.

Interaction:

Effect of the use of other drugs on rosuvastatin

Inhibitors of transport proteins

Rosuvastatin binds to some transport proteins, in particular, to OATP1B1 and BCRP. Concomitant use of drugs that are inhibitors of these transport proteins may be accompanied by an increase in the concentration of rosuvastatin in plasma and an increased risk of myopathy.

Cyclosporin

With simultaneous application of rosuvastatin and cyclosporine AUC rosuvastatin increased in 7 times in comparison with the values obtained in healthy volunteers (see section "Contraindications").Simultaneous use of drugs does not affect the concentration of cyclosporine in the blood plasma.

Inhibitors of the human immunodeficiency virus (HIV) protease

Despite the fact that the exact mechanism of interaction is unknown, joint administration of rosuvastatin with HIV protease inhibitors can lead to a significant increase in exposure to rosuvastatin. In a pharmacokinetic study, while taking 20 mg of rosuvastatin and a combined preparation containing two HIV protease inhibitors (400 mg of lopinavir / 100 mg of ritonavir), a 2-fold increase in AUV was observed in healthy volunteers_0-24) and 5 times the C_max rosuvastatin. Therefore, simultaneous administration of rosuvastatin and HIV protease inhibitors in the treatment of patients with HIV is not recommended.

Gemfibrozil and other lipid-lowering agents

The simultaneous use of rosuvastatin and gemfibrozil leads to an increase in 2 times C_max and AUC of rosuvastatin (see section "Special instructions"). Based on the data of the study of specific interactions, no pharmacokinetically significant interaction with fenofibrate is expected, but pharmacodynamic interaction is possible. Gemfibrozil, fenofibrate, other fibrates and a nicotinic acid in lipid-lowering doses (1 g or more per day) with simultaneous use with HMG-CoA reductase inhibitors increased the risk of myopathy, possibly due to the fact that they can cause myopathy and when used as monotherapy. Simultaneous administration of 40 mg rosuvastatin and fibrates is contraindicated (see section "Special instructions" and "Contraindications"). When taking the drug with gemfibrozil and other hypolipidemic drugs at a dose of more than 1 g / day, the initial dose of the drug containing rosuvastatin, should not exceed 5 mg.

Ezetimibe

Simultaneous application of rosuvastatin in a dose of 10 mg and ezetimibe at a dose of 10 mg shows an increase AUC rosuvastatin in patients with hypercholesterolemia. It is impossible to exclude an increase in the risk of side effects due to this pharmacodynamic interaction.

Antacids

The simultaneous use of rosuvastatin and suspensions of antacids containing aluminum or magnesium hydroxide can lead to a decrease in the concentration of rosuvastatin in the blood plasma by approximately 50%. This action is less pronounced if antacids are administered 2 hours after rosuvastatin administration.The clinical significance of this interaction has not been studied.

Erythromycin

The simultaneous administration of rosuvastatin and erythromycin leads to a decrease AUC rosuvastatin by 20% and Stach of rosuvastatin by 30%. Such interaction can be caused by increased intestinal motility caused by the administration of erythromycin.

Isozymes of cytochrome P450

Research results in vitro and in vivo showed that rosuvastatin is neither an inhibitor nor an inducer of cytochrome P450 isoenzymes. Besides, rosuvastatin is a rather weak substrate for these enzymes. Therefore, interaction of rosuvastatin with other drugs at the metabolic level with the participation of cytochrome P450 isoenzymes is not expected. There was no clinically significant interaction between rosuvastatin and fluconazole (inhibitor of isoenzymes CYP2C9 and CYP3A4) and ketoconazole (inhibitor of isoenzymes CYP2A6 and CYP3A4).

Fusidic acid

No studies have been conducted. As with the reception of other statins, post-marketing reports were received on cases of rhabdomyolysis in the joint administration of rosuvastatin and fusidic acid.It is necessary to closely monitor these patients. If necessary, a temporary discontinuation of rosuvastatin is possible.

Interaction with medicines, which requires dose adjustment for rosuvastatin

The dose of rosuvastatin should be adjusted if the instruction on the use of the drug indicates the effect on the exposure of rosuvastatin. If the exposure is expected to be 2 times or more, the initial dose of the drug should be 5 mg once a day. Also, the maximum daily dose of rosuvastatin should be adjusted so that the expected exposure to rosuvastatin does not exceed that for a dose of 40 mg taken without the simultaneous administration of medications interacting with rosuvastatin. For example, the maximum daily dose of the drug with simultaneous use with gemfibrozil is 20 mg (1.9 times increase in exposure), with ritonavir / atazanavir 10 mg (increase in exposure 3.1 times).

The effect of concomitant therapy on AUC rosuvastatin (results of published clinical trials)

Complementary therapy regimen	Mode of taking rosuvastatin	Change AUC rosuvastatin
Cyclosporine 75-200 mg 2 times a day, 6 months	10 mg once a day, 10 days	An increase of 7.1 times
Atazanavir 300 mg / ritonavir 100 mg, once a day, 8 days	10 mg once	Increase 3.1-fold
Symeprevir 150 mg once a day, 7 days	10 mg once	An increase of 2.8 times
Lopinavir 400 mg / ritonavir 100 mg, twice daily, 17 days	20 mg once a day, 7 days	An increase of 2.1 times
Clopidogrel 300 mg (loading dose), then 75 mg after 24 hours	20 mg once	2 times increase
Gemfibrozil 600 mg 2 times a day, 7 days	80 mg once	Increase 1.9 times
Eltrombopag 75 mg once a day, 10 days	10 mg once	Increase 1.6 times
Darunavir 600 mg / ritonavir 100 mg, 2 times a day, 7 days	10 mg once a day, 7 days	Increase by 1.5 times
Tipranavir 500 g / ritonavir 200 mg, 2 times a day, 11 days	10 mg once	Increase by 1.4 times
Dronedarone 400 mg twice daily	No data	Increase by 1.4 times
Itraconazole 200 mg once a day, 5 days	10 or 80 mg once	Increase by 1.4 times
Ezetimibe 10 mg once a day, 14 days	10 mg once a day, 14 days	Increase by 1.2 times
Fosamprenavir 700 mg / ritonavir, 100 mg, 2 times a day, 8 days	10 mg once	Without changes
Aleglitazar 0.3 mg, 7 days	40 mg, 7 days	Without changes
Silymarin 140 mg 3 times a day, 5 days	10 mg once	Without changes
Fenofibrate 67 mg 3 times a day, 7 days	10 mg, 7 days	Without changes
Rifampin 450 mg once a day, 7 days	20 mg once	Without changes
Ketoconazole 200 mg 2 times a day, 7 days	80 mg once	Without changes
Fluconazole 200 mg once a day, 11 days	80 mg once	Without changes
Erythromycin 500 mg 4 times a day, 7 days	80 mg once	Decrease by 28%
Baikalin 50 mg 3 times a day, 14 days	20 mg once	Decrease by 47%

Effect of rosuvastatin on other drugs

Antagonists of vitamin K

The beginning of rosuvastatin therapy or an increase in the dose of the drug in patients receiving both vitamin K antagonists (for example, warfarin) can lead to an increase in the international normalized relationship (INR). Removing rosuvastatin or lowering the dose may result in a decrease in INR. In such cases, monitoring of INR is recommended.

Oral contraceptives / hormone replacement therapy

The simultaneous administration of rosuvastatin and oral contraceptives increases AUC ethinylestradiol and AUC norgestrel by 26% and 34% respectively. This increase in plasma concentration should be considered when choosing a dose of oral contraceptives. Pharmacokinetic data on the simultaneous use of rosuvastatin and hormone replacement therapy are not available, therefore,You can not exclude a similar action when using this combination. However, this combination of drugs was widely used during clinical trials and was well tolerated by patients.

Other medicines

No clinically significant interaction between rosuvastatin and digoxin is expected.

Special instructions:

Renal Effects

In patients receiving high doses of rosuvastatin (mainly 40 mg), tubular proteinuria was observed, which in most cases was transient. Such proteinuria did not indicate an acute kidney disease or progression of kidney disease. The frequency of serious impairment of kidney function is increased by taking 40 mg rosuvastatin. In patients taking the drug at a dose of 40 mg, it is recommended to monitor the indicators of kidney function.

From the side of the musculoskeletal system

With the use of rosuvastatin in all doses, and especially when taking doses above 20 mg, myalgia, myopathy, and in rare cases rhabdomyolysis were detected.

Determination of creatine phosphokinase (CK)

Determination of the activity of CKK should not be performed after intensive physical exertion or in the presence of other possible causes of increased activity of CK, which may lead to incorrect interpretation of the results.If the initial level of CK is significantly increased (more than 5 times higher than the upper limit of the norm), after 5-7 days, a second measurement should be made. Do not start therapy if the repeated measurement confirms the baseline CK index (5 times higher than the upper limit of the norm).

Before the start of therapy

In appointing rosuvastatin, as well as the appointment of other inhibitors of HMG-CoA reductase, caution should be exercised in patients with existing risk factors for myopathy / rhabdomyolysis (see section "C caution"), it is necessary to consider the relationship between risk and the possible benefits of therapy and conduct clinical monitoring.

During therapy

The patient should be informed of the need to immediately notify the physician of cases of sudden onset of muscle pain, muscle weakness, or spasms, especially in combination with malaise or fever. In such patients, it is necessary to monitor the activity of CK. Treatment should be discontinued if the level of CK is more than 5 times higher than the upper limit of the norm or if the symptoms from the muscles are pronounced and cause daily discomfort, even if the activity of CK is increased by no more than 5 times compared with the upper limit of the norm.If symptoms disappear and CPK activity returns to normal, consideration should be given to re-administration of rosuvastatin or other inhibitors of GMC-CoA reductase in smaller doses with careful monitoring of the patient.

Routine monitoring of the activity of CKK in the absence of symptoms is inappropriate.

Very rare cases of immune-mediated necrotizing myopathy with clinical manifestations in the form of persistent weakness of proximal muscles and increased activity of CKK in blood serum during treatment or with stopping of taking statins, including rosuvastatin, have been noted. It may be necessary to conduct additional studies of the muscular and nervous system, serological studies, as well as therapy with immunosuppressive drugs. There were no signs of an increased effect on skeletal musculature with rosuvastatin and concomitant therapy. However, an increase in the incidence of myositis and myopathy was reported in patients taking other HMG-CoA reductase inhibitors together with fibrin acid derivatives, including gemfibrozil, ciclosporin, nicotinic acid in lipid-lowering doses (more than 1 g / day), azole antifungal agents, HIV protease inhibitors and macrolide antibiotics. Gemfibrozil increases the risk of myopathy when combined with certain HMG-CoA reductase inhibitors. Thus, simultaneous use of rosuvastatin and gemfibrozil is not recommended. The risk-to-benefit ratio should be carefully evaluated when rosuvastatin and fibrates or lipid-lowering doses are combined with nicotinic acid. Contraindicated taking rosuvastatin 40 mg together with fibrates (see sections "Interaction with other medicinal products and other forms of drug interactionand "Contraindications"). In 2-4 weeks after the start of treatment and / or with an increase in the dose of rosuvastatin, control of lipid metabolism parameters is necessary, if necessary, dose correction is required.

Liver

It is recommended to carry out the determination of liver function indices before the start of therapy and 3 months after the start of therapy. If the activity of "hepatic" transaminases in the blood serum is 3 times higher than the upper limit of the norm, rosuvastatin should be stopped or the dose reduced.

In patients with hypercholesterolemia due to hypothyroidism or nephrotic syndrome, therapy of the underlying disease should be performed prior to the initiation of treatment with rosuvastatin.

Special Populations. Ethnic groups

During pharmacokinetic studies among patients of Chinese and Japanese origin an increase in the systemic concentration of rosuvastatin was noted in comparison with the values obtained among patients - representatives of the Caucasoid race (see the section "Method of administration and dose " and "Pharmacokinetics").

HIV protease inhibitors

The simultaneous use of rosuvastatin with HIV protease inhibitors is not recommended (see "Interaction with other drugs and other types of interaction ").

Lactose

Do not use the drug in patients with lactase deficiency, intolerance to galactose and glucose-galactose malabsorption.

Interstitial lung disease

With the use of some statins, especially for a long time, there have been reports of single cases of interstitial lung disease. Manifestations of the disease may include shortness of breath, dry cough and deterioration in overall health (weakness, weight loss and fever).If suspicion of interstitial lung disease should be stopped by statin therapy.

Increase in the concentration of glucose in the blood

Preparations of the class of statins can cause an increase in the concentration of glucose in the blood. In some patients at high risk of developing diabetes, such changes can lead to its manifestation, which is an indication for the appointment of hypoglycemic therapy. However, a reduction in the risk of vascular disease with statins is greater than the risk of developing diabetes, so this factor should not serve as a basis for the abolition of statin treatment. For patients at risk (fasting blood glucose 5,6-6,9 mmol / l, BMI> 30 kg / m², triglyceridemia, history of arterial hypertension), medical supervision should be established and biochemical parameters monitored regularly.

Effect on the ability to drive transp. cf. and fur:

Care should be taken when driving vehicles and mechanisms and occupations requiring increased concentration and speed of psychomotor reactions (dizziness may occur during therapy).

Form release / dosage:

Film-coated tablets, 5 mg, 10 mg, 20 mg and 40 mg.

Packaging:

For 7 tablets in a blister of (PVC / Al / PA) foil / aluminum foil. For 4 blisters together with instructions for use in a pack of cardboard.

For 10 tablets in a blister of (PVC / Al / PA) foil / aluminum foil. For 3 blisters together with instructions for use in a pack of cardboard.

Storage conditions:At a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-003985

Date of registration:01.12.2016

Expiration Date:01.12.2021

The owner of the registration certificate:Dr. Reddy's Laboratories Ltd.Dr. Reddy's Laboratories Ltd. India

Manufacturer: & nbsp

DR. REDDY`S LABORATORIES, LTD. India

Representation: & nbspDr. Reddy`c Laboratoris Ltd.Dr. Reddy`c Laboratoris Ltd.

Information update date: & nbsp13.01.2017

Illustrated instructions

Instructions

Reddistatin (Reddistatine)